Psychedelic treatment and mental health: Navigating a longer trip with optimism

[This article is part of the 2025 Trends Report]

Although a much-anticipated psychedelic treatment did not receive approval in 2024, the research community is forging ahead with efforts to demonstrate the vital potential for these nontraditional drugs in mental health treatment.

In August, the U.S. Food and Drug Administration (FDA) rejected an application from Lykos Therapeuticsopens in new window to approve MDMA (3,4-methylenedioxymethamphetamine, also called Ecstasy or Molly) in combination with therapy for treatment-resistant posttraumatic stress disorder (PTSD). The drug would have become the first psychedelic approved by the FDA, which requested additional research to show the treatment is safe and effective. Although the FDA’s letter to Lykos is not public, an advisory committee had previously cited concerns such as difficulty evaluating the benefits of the therapy component and trouble creating a truly “blinded” experiment. The mind-altering effects, the committee worried, meant participants were more likely to predict if they had received the drug or a placebo, which could skew results.

During a congressional roundtable on psychedelic-assisted therapy in September 2024, APA leaders highlighted the need for quality, unbiased research as well as care models that include a psychotherapy component. APA is also updating the 2017 Clinical Practice Guideline for the Treatment of PTSD in Adults.

Though more research is needed, scientists are optimistic that there is still a clear path to approval for MDMA, psilocybin, LSD (lysergic acid diethylamide), and other psychedelics in the coming years. “The FDA determination for MDMA was one decision for one drug for one sponsor for one application,” said Fred Barrett, PhD, director of the Center for Psychedelic and Consciousness Research at Johns Hopkins University. “This is really just the beginning. For the FDA to gain confidence, there will likely need to be studies with multiple designs that show these drugs are safe and effective.”

Researchers involved in clinical trials with psychedelics contend that issues of blinding are common in other studies of mental health treatments not involving psychedelics, such as antidepressant medications.

While federal regulators await more clinical trial data, new studies are shedding light on how psychedelics alter the brain to facilitate lasting improvements related to substance use disorders, PTSD, depression, anxiety, and other conditions. The latest evidence suggests that these drugs influence neural connections associated with a sense of identity and memory to help people overcome maladaptive behaviors.

As researchers hone their understanding of the neurobiological mechanisms involved in psychedelic treatment and patient demand continues to grow, psychological scientists have a crucial role in guiding the field. “There is a lot of potential, but people are prone to thinking this is a magic pill that can solve their problems,” said Mia Sarno, PsyD, a licensed clinical psychologist and a study therapist who assists with clinical trials for psychedelics. “Psychologists are uniquely positioned to provide leadership because we are experts in assessment, research, ethics, and the study of consciousness.” Sarno believes the field of psychology has an opportunity and a responsibility to ensure safe delivery of psychedelic-assisted therapy to individuals suffering from mental health conditions.

The latest research findings are providing clues as to how psychedelics increase synaptic connections in the brain, and how clinicians can help patients take advantage of this neuroplasticity to combat treatment-resistant mental health conditions. In one study, researchers scanned the brains of healthy adults before, during, and 3 weeks after a high dose of psilocybin and again 6 to 12 months later. Controls were given methylphenidate, a drug to treat attention-deficit/hyperactivity disorder (ADHD). During the psychedelic dosing session, the scans showed that neural pathways associated with the default mode network—which creates a sense of identity and self—were “desynchronized,” or disrupted (Siegel, J. S., et al. Nature, Vol. 632, 2024opens in new window).

After the “trip,” most brain activity returned to normal, but there was a lasting reset in the connection between the hippocampus—the hub of memories—and the default mode network.

“Putting these parts of the brain into a more plastic and adaptable state seems to help people change behavior,” said Joshua Siegel, MD, PhD, a neuroscientist who is first author of the study and an assistant professor in the Center for Psychedelic Medicine at New York University’s Grossman School of Medicine. “When therapy is used in this setting, it allows people to take advantage of this increased flexibility to overcome maladaptive patterns.”

The role of psychedelics in memory was also the focus of a recent study of multiple drugs, including sedatives, cannabinoids, and stimulants. Psychedelics impaired the formation of hippocampal episodic memories, which is the recollection of experiences in the context of time, place, and emotions (Psychological Review, Vol. 131, No. 2, 2024opens in new window). Cortical familiarity memory, however, was enhanced on higher doses of psychedelics. These are memories without the details of when or where, such as a person who looks familiar but cannot be placed. “Taking the hippocampus offline may be a useful way to learn how to create new cortical learning and override behaviors that have arisen over time,” said Manoj Doss, PhD, lead author of the study and a research fellow in the Center for Psychedelic Research and Therapy at The University of Texas at Austin Dell Medical School.

The possibility that psychedelics might reopen “critical periods” of learning development and memory formation was also the focus of a study that aimed to teach mice social skills. The researchers trained mice to differentiate between an environment associated with social interaction and one associated with being alone. The mice that received a psychedelic drug preferred the social setting, a behavior they usually learn as juveniles (Nardou, R., et al. Nature, Vol. 618, 2023opens in new window). This critical period of learning lasted 2 weeks with psilocybin and MDMA, and 3 to 4 weeks with LSD and ibogaine. This timing was similar to how people self-report the acute effects of each psychedelic drug. The investigators also identified which genes were expressed during this open critical period. They found that about one fifth of these genes regulate proteins involved in maintaining or repairing a part of the brain associated with learning behaviors that respond to rewards.

While priming the brain to learn new, healthy behaviors has the potential to help patients, these findings highlight the importance of providing therapeutic guidance for this form of treatment. “We need to direct what people are learning to some degree so we are not introducing false beliefs,” Doss said.

Even as the number of studies of psychedelics grows, scientists acknowledge the need to confront challenges with finding the ideal research patient population. In late 2022, a team at Massachusetts General Hospital’s Center for the Neuroscience of Psychedelics began screening potential participants for a study that would assess the effects of a single dose of psilocybin on rumination and brain activity. They were looking for people with treatment-resistant depression, defined as failure to respond to two or more antidepressant regimens despite adequate dose and duration. Many potential participants were eliminated because they had not had two adequate trials of antidepressant medications. The study also required participants to abstain from cannabis for 18 weeks, but the researchers discovered that many potential participants used cannabis regularly, which was an exclusion criterion. The team screened 700 people, and not one person met the inclusion and exclusion criteria.

“It was very sobering to realize that so many people were undertreated and continued to suffer,” said Sharmin Ghaznavi, MD, PhD, who is leading the study. To increase the chances of finding participants, Ghaznavi edited the inclusion/exclusion criteria for the protocol to allow one failed trial of an antidepressant instead of two, and she received approval from the FDA to move ahead with the study. “We are more optimistic about recruitment with this change,” she said.

Researchers will also need to study more diverse participant pools. Most of the findings related to psychedelics are also drawing conclusions from studies that involve largely affluent, educated, White participants. In one review of 39 studies published from 1994 to 2024, more than 85% of participants identified as non-Hispanic White, with 3.1% Black, 6.8% Latinx/Hispanic, 3.6% Asian, and 1.2% Indigenous (The Lancet: eClinicalMedicine, Vol. 74, 2024opens in new window). “We cannot necessarily surmise that people from other backgrounds will respond the same way,” said study author Albert Garcia-Romeu, PhD, associate director of the Center for Psychedelic and Consciousness Research at Johns Hopkins University.

To increase diversity in psychedelic clinical trials, Garcia-Romeu urges researchers to consider building connections with community organizations, places of worship, and other groups to create collaborative approaches to engage community members in research efforts.

Although federal approval of psychedelics is still pending, evidence suggests that patients are eager to learn more about these treatments now. According to a recent study of more than 200 mental health providers in California, nearly half reported that patients asked them for advice about psychedelics (Clinical Psychology & Psychotherapy, Vol. 30, No. 6, 2023opens in new window). The vast majority of providers in the study were largely supportive of psychedelic use for psychotherapy and treatment of psychiatric disorders. But nearly half of the providers did not feel comfortable addressing questions from patients about how psychedelics might affect them. “The clinicians felt that they were not informed enough about this topic,” said Nancy Haug, PhD, a professor in the department of psychology at Palo Alto University and senior author on the paper. “More education about the risks and benefits of psychedelic use is needed.” Under current billing and payment models, nonprescribing psychologists would not be able to prescribe psychedelics even if these drugs receive FDA approval.

Numerous training programs in the United States teach mental health professionals about the history of psychedelics, the different substances available, the safety issues, contraindications, how to integrate therapy into treatment, and more. To equip the psychology workforce to support patients, a group of psychologists across six APA divisions plans to roll out a free toolkit and series of webinars in 2025 that will cover the current research, foundational elements, ethical considerations, and models of care for this type of treatment, according to Sarno. She said psychologists can get involved in psychedelic-assisted therapy through ketamine clinics, through FDA clinical trials, or by offering psychedelic integration therapy to patients who receive dosing in another setting.

Informed clinicians can also help guide standards of care as psychedelics become more common in medical settings. “This model of care is somewhat different than traditional psychotherapy,” said Sarno. “There are additional ethical considerations when working with people in nonordinary states of consciousness.” Patients may be at increased risk of transference and countertransference and more vulnerable to power dynamics with their providers. For their part, providers may also need to hold nonjudgmental space for patient experiences they have never seen before, Sarno said. They may see patients shaking, moving erratically, or making noises like yelling or screaming. Patients can also experience hallucinations, such as visions of humans, nonhuman entities, or geometric shapes and colors.

Psychologists can also pave the way for safe practices by advocating for thoughtful, informed consent processes related to psychedelic treatment, said Haug. For example, physical touch—which is not typically part of psychotherapy—can sometimes be used to provide reassurance during a dosing session. This may include holding hands or placing a hand on a patient’s shoulder. The process of consent should include opportunities for patients to practice exercising their choices, such as declining touch from the therapist.

Although psychedelic-assisted therapy has yet to clear federal regulatory hurdles, patients are seeking out this type of treatment regardless. For patients suffering from treatment-resistant conditions, receiving guidance from a knowledgeable, nonjudgmental health provider about psychedelics could help them make educated decisions. “If someone with PTSD attempted suicide twice, then I consider their condition life-threatening,” said Jennifer Mitchell, PhD, lead author of a recent Phase 3 clinical trial of MDMA-assisted therapy for PTSD and a professor in the departments of neurology and psychiatry and behavioral services at University of California, San Francisco. “If the individual is well informed about the potential risks and the safest way to access psychedelic treatment, they should have the right to try—just as cancer patients at the end of life have the right to enroll in clinical trials.”